Adult stem cells are extremely important for long-term tissue homeostasis throughout life. Their self-renewing proliferative capacity involves numerous tightly coordinated processes to ensure preservation of genome integrity during cell division. The regulatory mechanisms underlying their aging are less well defined. Nonetheless, global gene expression studies of stem cells purified from young and old mice have implicated the involvement of epigenetic regulation in higher-order chromatin dynamics. These studies have suggested coordinated age-dependent regulation of chromosomal regions, chromatin remodeling activities and lineage specification genes (Chambers et al. (2007) PLoS Biol., 5: e201; Rossi et al. (2007) Exp. Gerontol., 42: 385-390; Rossi et al. (2005) Proc. Natl. Acad. Sci. USA, 102: 9194-9199).
All cells are constantly challenged by exogenous and endogenous sources of DNA damage; depending on the nature of the damage, they activate different DNA damage repair mechanisms (Sinclair et al. (2004) Am. Nat., 164: 396-414). In parallel, cells also activate checkpoint pathways, which delay cell cycle progression until genome integrity has been restored (Shiloh (2001) Curr. Opin. Genet. Dev., 11: 71-77). One aspect of the stem cell hypothesis of aging postulates that the gradual and coordinated age-related loss of DNA damage repair capacity results in DNA damage accumulation over time. This damage would pose a significant threat to adult stem cell survival by altering proliferation and differentiation patterns, ultimately triggering cellular senescence. Therefore, the ability of adult stem cells to monitor and faithfully repair DNA damage is key to the prevention of aging and neoplastic transformations.
Little is known about the precise relationship between chromatin and DNA-repair factors. More than 50% of the human genome consists of retrotransposons (Lander et al. (2001) Nature, 409: 860-921). Their epigenetic makeup is poorly understood and inadequately annotated at the genomic level, due to a high degree of sequence conservation. In fact, many retrotransposons are derived from ancestral RNA genes and might represent genetically active sequences that encode different types of RNA with yet unknown functions (McClintock (1956) Cold Spring Harb. Symp. Quant. Biol., 21: 197-216). However, clear evidence exists that the retrotransposal portion of the genome profoundly influences the organization, integrity, and evolution of the host's genome and transcriptome (Han et al. (2004) Nature, 429: 268-274; Kazazian (2004) Science, 303: 1626-1632). A growing body of evidence demonstrates that, during mammalian evolution, a large number of ancient retroelements acquired regulatory or structural functions.
The majority of retrotransposons are expressed in extraordinarily complex patterns in a cell- or tissue-specific manner, and potentially provide a rich source of non-protein coding RNAs to guide the trajectories of cellular differentiation and multicellular development (Amaral et al. (2008) Science 319: 1787-1789; Birney et al. (2007) Nature, 447: 799-816; Denoeud et al. (2007) Genome Res., 17: 746-759; Dinger et al. (2008) Genome Res., 18: 1433-1445; Dinger et al. (2008) J. Mol. Endocrinol., 40: 151-159; Emanuelsson et al. (2007) Genome Res., 17: 886-897; Faulkner et al. (2009) Nat. Genet., 41: 563-571; Lowe et al. (2007) Proc. Natl. Acad. Sci. USA, 104: 8005-8010; Mattick et al., (2009) Bioessays, 31: 51-59; Mercer et al. (2008) Proc. Natl. Acad. Sci. USA, 105: 716-721; Mikkelsen et al., ed. (2007) Genome-wide maps of chromatin state in pluripotent and lineage-committed cells; Rozowsky et al. (2007) Genome Res., 17: 732-745; Trinklein et al. (2007) Genome Res., 17: 720-731). Recent studies have proven that retrotransposon transcriptional activities trigger and guide the processes of (i) assembly of centromeric chromatin, (ii) gene transcription, (iii) compartmentalization of chromatin and, (iv) nuclear organization of chromatin insulation during X-chromosome inactivation. Retrotransposons also serve a distinct function in non-random chromosomal translocations in tumors (Allen et al. (2004) Nat. Struct. Mol. Biol., 11: 816-821; Chueh et al. (2005) Hum. Mol. Genet., 14: 85-93; Lei and Corces (2006) Cell, 124: 886-888; Lei and Corces (2006) Nat. Genet., 38: 936-941; Lin et al. (2009) Cell, 139: 1069-1083; Lunyak (2008) Curr. Opin. Cell Biol., 20: 281-287; Lunyak et al. (2007) Science, 317: 248-251; Mattick et al. (2009) Bioessays, 31: 51-59; Navarro et al. (2009) Epigenetics Chromatin 2: 8).
There is also a considerable amount of tissue-specific, development-specific, and disease-related variability in DNA methylation and covalent modifications of chromatin within the retrotransposal portion of the genome (Kondo and Issa (2003) J. Biol. Chem. 278: 27658-27662; Estecio et al. (2007) PLoS ONE 2: e399). A genome-wide study by Martens (Martens et al. (2005) EMBO J., 24: 800-812) demonstrates that LINEs, SINE/Alus, and other interspersed retrotransposons have variable degrees of H3K9, H3K27, and H4K20 histone methylation, raising the possibility that posttranscriptional modifications (PTM) of retrotransposal chromatin can influence diverse cellular processes.